Anthracyclines are compounds previously isolated and studied and which have shown activity as bacterial antibiotics and anti-cancer agents in mammalian chemotherapy. Most such anthracyclines are natural products derived from the bacterial species, Actinomycetes and Streptomycetes. Generally, such anthracyclines have the structure: ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 are usually --H, --OH or --OCH.sub.3. The R.sub.6 substituent is normally --H or a mono-or di-saccharide; while R.sub.7 is, most often, --OH, or a simple -amine or alkylamine. The ring structure designated "A" has a wide variation in the R.sub.4 and R.sub.5 substituents. R.sub.4 may range from --H to a-carboxyl ester; while R.sub.5 may be --CH.sub.2 CH.sub.3, ##STR2## Where the R.sub.5 substituent is --CH.sub.2 CH.sub.3, the commercial products are known as Cinerubin or Aclacinomycin; where it is --COCH.sub.3, the commercial products are known as Daunorubicin; where --COCH.sub.2 OH, as Adriamycin; and where a C.dbd.NNHCO.phi., as Rubidazone.
While many anthracyclines have been produced, most exhibit low effectiveness or potency against neoplasms, or produce unacceptable side effects. On the other hand, some anthracyclines, such as the aforementioned Daunorubicin and Adriamycin find clinical use in the treatment of various types of cancer. It appears that those anthracyclines in which R.sub.1 is --H or sometimes OH are quite toxic compared to those with --OCH.sub.3. Where R.sub.3 is a methoxy group, the anti-cancer activity appears to be less than where R.sub.3 is the hydroxy group. In addition, most anthracyclines produce accumulative toxicity to vital tissues such as bone marrow and heart. While over one hundred analogs are now known, most are less potent and less effective than the four or five clinically useful analogs.
It is theorized that the anthracyclines block the functions of the deoxyribonucleic acids (DNA) by insertion of their BCD aromatic ring region in between successive base pairs of the DNA structure. Thus it appears that the drug effectiveness relies upon the binding thereof to a site on the receptor DNA molecule and/or other receptor molecules. Some evidence suggests that the drug acts only so long as it is bound to the receptor site and is made inactive as soon as it dissociates therefrom. It also appears that if it were possible to assure that a greater number of closely related receptor sites were drug-occupied, effectiveness would be greatly enhanced. Unfortunately, there is a vanishingly small probability that two drug molecules ingested at the same time will arrive simultaneously at related receptor sites and both remain simultaneously bound thereto.
On the other hand, if either drug molecule is attached to a similar drug molecule, then as it arrives at the receptor area it will increase the chance of two-receptor interactions occurring at almost the same time by an enormous factor. The further chance that both will dissociate from their respective receptor sites at the identical moment is also greatly reduced. In addition, each time one part of the molecule begins to dissociate the attachment of the other part of the molecule will enhance the opportunity that the dissociating part will re-attach. It appears therefore that a drug with multiple receptor sites binding ability could potentially be much more potent and effective than a drug having only one receptor site binding structure. Although the drugs disclosed herein are anthracyclines, this principle has obvious application to other drug classes.
In addition to the ability to effectively attach to binding sites on the cell DNA, and other receptor molecules, drug effectiveness is very much related to its toxicity against the tissues of the disease-free or normal portions of the organism. It is therefore desirable to protect the normal portions of the organism from the drug, yet at the same time, effectively direct the drug specifically against the diseased tissues of the organism. Any means of selectively directing the drug to the diseased portions while bypassing the disease-free portions of the organism will greatly benefit the effectiveness of any therapeutic methods. In addition, such method should enable the use of lower dosages relative to the weight of the organism as a whole but, yet supplies sufficient drug at the diseased sites to produce a high level of activity against the diseased portions of the organism. Lower dosage rates combined with careful "targeting" of the drug to the diseased site will obviously greatly diminish undesired side effects to the organism.
It should be understood that while the theories expressed above may underlie the demonstrated effectiveness of the drug and treatment method disclosed hereinafter, its accuracy should in no way be taken to limit the fact that the bis-anthracyclines and liposome delivery method disclosed hereinafter truly demonstrate an improvement over previously known related drugs and methods.